Etiology and prognosis of spondyloarthropathies using family-based epidemiological methods

Abstract: The spondyloarthropathies (SpA) are a group of chronic inflammatory diseases that share several disease characteristics such as inflammation of entheses and extramusculoskeletal manifestations like uveitis, psoriasis, and inflammatory bowel disease. These diseases, or symptoms thereof, are also known to run in families. The purpose of this thesis was to expand knowledge concerning the etiology and prognosis of SpA, using family-based epidemiological methods on data from Swedish health and population registers. In study I, we estimated the familial aggregation of a specific SpA subtype, ankylosing spondylitis (AS), in a nested case-control study of AS cases, population controls, and first-degree relatives of both groups. We were able to provide a precise estimate of the familial aggregation, corresponding to a 20-fold increased risk of AS among first-degree relatives of AS cases. We also estimated the heritability of AS to 77%, i.e. the proportion of susceptibility to AS in the population that is due to genetics. Our estimate can be seen as an upper limit for the heritability, as shared environmental effects were not considered. While both estimates are relatively high, they are lower than previous reports for AS, which have been based on small and often selected samples. In study II, a cohort study, we investigated whether family history of SpA, or its specific subtypes, were predictive of response to treatment with tumor necrosis factor inhibitors (TNFi) in patients with SpA. Despite being such a strong risk factor for disease development, we did not find family history to be associated with prognosis in terms of TNFi drug survival or treatment response at three or twelve months. In study III, we studied temporal trends in pregnancy outcomes among women with axial SpA. We found that women with axial SpA, compared to women from the general population, were at increased risk of pre-eclampsia, preterm birth, and serious infection in the infant. The proportion of cesarean deliveries was also significantly higher among women with axial SpA. The risks had, however, diminished over the last decade, to reach similar levels as in the general population, while the use of effective treatment in the form of TNFi increased before and during pregnancy over the same period. In study IV, we searched for environmental risk factors for AS, with a focus on perinatal characteristics and infections in childhood. In this nested case-control study, we found that having older siblings and a history of tonsillectomy in childhood were associated with AS in adulthood, even after adjustment for childhood socio-economic status and other family-shared confounders through a sibling comparison. By using data from national registers, we were able to perform the hitherto largest studies on these topics regarding etiology and prognosis of SpA. While the genetic influence is substantial in AS, there is a larger contribution of environmental risk factors than previously known. These seem partly related to early life, with a possible influence of childhood infections. We have also added to a growing body of evidence supporting the use of effective treatment in women with axial SpA, before and at least in the beginning of pregnancy, to minimize the risks active that SpA disease pose on pregnancy outcomes.